Transdermal delivery of beneficial substances effected by a hostile biophysical environment

ABSTRACT

The present invention generally relates to the transdermal delivery of substances and, in some embodiments, to the transdermal delivery of beneficial substances by a hostile biophysical environment. In one aspect, various methods for the transdermal delivery of beneficial substances are disclosed. By creating a hostile biophysical environment, beneficial substances may be delivered, according to certain embodiments, through the stratum corneum of the skin into the body. Beneficial substances include, but are not limited to, pharmaceutical agents, drugs, vitamins, co-factors, peptides, dietary supplements, and others. The beneficial effects disclosed include, for instance, relief of pain and inflammation, prevention and healing of ulcers of the skin, relief of headache, improved sexual function and enjoyment, growth of hair on the scalp, improving muscle size and/or function, removing body fat and/or cellulite, treating cancer, treating viral infections and others. A hostile biophysical environment may also be used in conjunction with systems and methods for increasing local blood flow, according to one set of embodiments. For example, by using a nitric oxide donor such as L-arginine, local blood flow may be increased, e.g., by transdermally delivering the nitric oxide precursor. The nitric oxide donor may be the sole cause of increased blood flow, or it may be supplemented with an adjunct such as theophylline.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/587,323, filed Oct. 19, 2006, entitled “Transdermal Delivery ofBeneficial Substances Effected by a Hostile Biophysical Environment,” byE. T. Fossel, which application is a national stage filing under 35U.S.C. §371 of International Patent Application Serial No.PCT/US2005/013228, filed Apr. 19, 2005, which application claims thebenefit of U.S. Provisional Patent Application Ser. No. 60/563,573,filed Apr. 19, 2004, entitled “Flow Assisted Transdermal Preparations ofEphedra and Ephedra Components to Avoid Adverse Effects,” by E. T.Fossel; U.S. Provisional Patent Application Ser. No. 60/563,575, filedApr. 19, 2004, entitled “Flow Assisted Transdermal Delivery of AnabolicSteroids,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,574, filed Apr. 19, 2004, entitled “Augmented Flow AssistedTransdermal Delivery of Anabolic Steroids,” by E. T. Fossel; U.S.Provisional Patent Application Ser. No. 60/563,558, filed Apr. 19, 2004,entitled “Flow Assisted Topical Transdermal Methods of Drug Delivery,”by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,559, filed Apr. 19, 2004, entitled “Transdermal Delivery ofPharmaceutical Agents Effected by a Hostile Biophysical Environment,” byE. T. Fossel; U.S. Provisional Patent Application Ser. No. 60/563,560,filed Apr. 19, 2004, entitled “Transdermal Drug Delivery by Means of aHigh Ionic Strength Environment,” by E. T. Fossel; U.S. ProvisionalPatent Application Ser. No. 60/563,576, filed Apr. 19, 2004, entitled“Transdermal Delivery of Ephedra and Ephedra Components by Use of AHostile Biophysical Environment,” by E. T. Fossel; U.S. ProvisionalPatent Application Ser. No. 60/563,572, filed Apr. 19, 2004, entitled“An Augmented Flow Assisted Preparation to Increase Muscle Size andPerformance,” by E. T. Fossel; U.S. Provisional Patent Application Ser.No. 60/563,564, filed Apr. 19, 2004, entitled “A Flow AssistedPreparation to Increase Muscle Size and Performance,” by E. T. Fossel;U.S. Provisional Patent Application Ser. No. 60/563,570, filed Apr. 19,2004, entitled “Transdermal Preparations to Improve Muscle Function andSize,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,561, filed Apr. 19, 2004, entitled “Use of a Silicon Based Matrixfor Transdermal Delivery of L-Arginine and Adjuncts to Cause BeneficialEffects,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,562, filed Apr. 19, 2004, entitled “Transdermal Preparation ofIbuprofen to Reduce Pain and Inflammation,” by E. T. Fossel; U.S.Provisional Patent Application Ser. No. 60/563,567, filed Apr. 19, 2004,entitled “A Transdermal Augmented L-Arginine Preparation for Treatmentof Headache,” by E. T. Fossel; U.S. Provisional Patent Application Ser.No. 60/563,552, filed Apr. 19, 2004, entitled “Flow Assisted TopicalTransdermal Method of Drug Delivery of Drugs with Systemic Toxicity,” byE. T. Fossel; U.S. Provisional Patent Application Ser. No. 60/563,569,filed Apr. 19, 2004, entitled “Transdermal Delivery of SystematicallyToxic Pharmaceutical Agents Effected by a Hostile BiophysicalEnvironment,” by E. T. Fossel; and U.S. Provisional Patent ApplicationSer. No. 60/563,571, filed Apr. 19, 2004, entitled “Transdermal FlowAssisted Localized Delivery of Chemotherapeutic Agents,” by E. T.Fossel.

International Patent Application Serial No. PCT/US2005/013228 alsoclaims the benefit of U.S. Provisional Patent Application Ser. No.60/563,563, filed Apr. 19, 2004, entitled “Use of Transdermal L-Arginineand Adjuncts to Cause Beneficial Effects by Increasing Local BloodFlow,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,565, filed Apr. 19, 2004, entitled “Use of Arginine and ArginineDerivatives and Adjuncts to Improve Grafting of Real and ArtificialSkin,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,566, filed Apr. 19, 2004, entitled “Transdermal Delivery ofL-Arginine for the Purpose of Enhancing the Appearance of the FemaleBreast,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,553, filed Apr. 19, 2004, entitled “Use of A TransdermalL-Arginine and Adjuncts to Improve Bone Healing,” by E. T. Fossel; U.S.Provisional Patent Application Ser. No. 60/563,554, filed Apr. 19, 2004,entitled “Use of a Transdermal Preparation of L-Arginine and Adjuncts toEffect Wound Healing,” by E. T. Fossel; U.S. Provisional PatentApplication Ser. No. 60/563,555, filed Apr. 19, 2004, entitled “Use of aTransdermal Preparation of L-Arginine and Adjuncts to Facilitate Healingof Infection,” by E. T. Fossel; U.S. Provisional Patent Application Ser.No. 60/563,556, filed Apr. 19, 2004, entitled “Transdermal Delivery ofL-Arginine Preparation to Regress Neuropathy and Heal and PreventUlcers,” by E. T. Fossel; U.S. Provisional Patent Application Ser. No.60/563,557, filed Apr. 19, 2004, entitled “A Transdermal Preparation ofL-Arginine to Improve Flow in Peripheral Artery Disease and PreventClaudication,” by E. T. Fossel; and U.S. Provisional Patent ApplicationSer. No. 60/563,551, filed Apr. 19, 2004, entitled “Use of a TransdermalL-Arginine Preparation and Adjuncts to Improve Outcome in Transplant andPlastic Surgery,” by E. T. Fossel. Each of the above applications isincorporated herein by reference.

FIELD OF INVENTION

The present invention generally relates to the transdermal delivery ofsubstances.

BACKGROUND

Local transdermal delivery of drugs, while desirable, is limited bycurrent technologies. Few pharmaceutical entities have successfully beendelivered transdermally in effective dosages. For example, a limitednumber of drugs, such as steroids, nicotine and nitroglycerine, whichare non-charged and do not form hydrogen bonds, have been successfullydelivered by passive diffusion, relying on the concentration gradientbetween outside and inside the skin to deliver the agent in accordancewith Fick's first law of diffusion. The amount of pharmaceutical agentthat can be delivered through simple diffusion is also limited. Forinstance, once the concentration inside the stratum corneum becomesequal to that outside, flow of pharmaceutical agent may stop. Thus,improvements in the transdermal delivery of substances, locally orsystemically, are needed.

SUMMARY OF THE INVENTION

The present invention generally relates to the transdermal delivery ofsubstances, locally or systemically, and in some embodiments, to thetransdermal delivery of beneficial substances by a hostile biophysicalenvironment. The subject matter of the present invention involves, insome cases, interrelated products, alternative solutions to a particularproblem, and/or a plurality of different uses of one or more systemsand/or articles.

This invention relates, in one aspect, to the field of localizedtransdermal delivery of substances which have a beneficial effect, forexample, to the transdermal delivery of herbs, vitamins, minerals,pharmaceutical agents, drugs, peptides, dietary supplements, or othersubstances affected by a hostile biophysical environment. The hostilebiophysical environment may comprise a high ionic strength vehicle insome embodiments, and delivery may be enhanced, in certain cases, byvarious techniques to increase local blood flow at the delivery site.For instance, substances with localized action may avoid systemictoxicity if delivered locally and transdermally. In some cases, variousbeneficial substances which function at local sites, rather thansystemically, may be more efficaciously administered by transdermalrather than systemic administration. If the beneficial substance isdelivered through the skin, a higher dose in the tissue to be treatedmay be achieved. In addition, a substantially lower total body dose maybe achieved in some cases. This can be understood if one considers thenon-limiting example of treating pain in finger joints with a NSAID (anonsteroidal anti-inflammatory drug). If the pain is to be treatedsystemically, e.g., by oral administration, the whole body, includingthe finger joints, is dosed with the NSAID. The concentration of NSAIDis approximately the same throughout the body, including the fingerjoints. If, on the other hand, one were to apply the NSAID transdermallyto the finger joints, the rest of the body would not be dosed (or wouldbe dosed to a significantly lesser extent). Thus, the total dose oftransdermal NSAID would only be a fraction of the dosage required forsystemic administration.

In some embodiments, the beneficial substances delivered transdermallymay improve health, improve body function, or treat a variety of diseasestates.

In one set of embodiments, the invention relates to the field ofheadache treatment, and in some cases, to the use of arginine and/orarginine derivatives or adjuncts to provide effective headache relief.This invention also relates, in another set of embodiments, to the fieldof relief of pain and/or inflammation and in some cases, to atransdermal preparation of ibuprofen to reduce pain and/or inflammation.In certain instances, the ibuprofen is delivered from a vehicle into thetissue through the use of a hostile biophysical environment.

This invention also relates, in yet another set of embodiments, tosystems and methods for improving uptake of muscle improving agents, forexample, by increasing local blood flow by delivering a nitric oxidedonor such as L-arginine, either alone or with an adjunct such astheophylline. This invention also relates, in still another set ofembodiments, to topical methods of administrating anabolic steroids, forexample, steroids that exhibit unacceptable systemic toxicity. Thesteroids may also promote improved muscle size and function through theuse of enhanced blood flow.

This invention relates, in one set of embodiments, to topical methods ofadministering chemotherapeutic or antiviral agents, for instance, topromote healing or recovery, or to prevent recurrence of a localizedcancer or viral infection.

In yet another set of embodiments, this invention relates to the fieldof enhanced sexual function. In some cases, arginine and/or argininederivatives and adjuncts may be applied to increase genital blood flow,which may increase sexual function.

In one aspect, the invention is a method. The method includes, in oneset of embodiments, an act of applying, to a portion of the skin of asubject, a delivery vehicle comprising a pharmaceutical agent in ahostile biophysical environment.

In another aspect, the invention includes a delivery vehicle. In one setof embodiments, the delivery vehicle includes a nitric oxide donor, anda pharmaceutical agent at a dosage effective to treat a localizedmedical condition, wherein the dosage is lower than the effective dosageof the pharmaceutical agent when taken orally. In another set ofembodiments, the delivery vehicle includes a nitric oxide donor, and apharmaceutical agent able to treat one or more medical conditionsselected from the group consisting of cramps, pain, migraine, arthritis,swelling, sexual dysfunction, hair loss, skin ulcers, and migraine.

One aspect of the invention is directed to a method comprising an act ofadministering, to a subject, a delivery vehicle comprising a nitricoxide donor contained within a hostile biophysical environment. Anotheraspect of the invention is directed to an article comprising a creamcontaining a nitric oxide donor in a hostile biophysical environment.

Several methods are disclosed herein of administering a subject (whichmay be human or a non-human animal) with a composition for prevention ortreatment of a particular condition. It is to be understood that in eachsuch aspect of the invention, the invention specifically includes, also,the composition for use in the treatment or prevention of thatparticular condition, as well as use of the composition for themanufacture of a medicament for the treatment or prevention of thatparticular condition.

The present invention, in another aspect, is directed to a method ofmaking one or more of the embodiments described herein. In yet anotheraspect, the present invention is directed to a method of using one ormore of the embodiments described herein. In still another aspect, thepresent invention is directed to a method of promoting one or more ofthe embodiments described herein.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention. In cases where the present specificationand a document incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control. If twoor more documents incorporated by reference include conflicting and/orinconsistent disclosure with respect to each other, then the documenthaving the later effective date shall control.

DETAILED DESCRIPTION

The present invention generally relates to the transdermal delivery ofsubstances and, in some embodiments, to the transdermal delivery ofbeneficial substances by a hostile biophysical environment. In oneaspect, various methods for the transdermal delivery of beneficialsubstances are disclosed. By creating a hostile biophysical environment,beneficial substances may be delivered, according to certainembodiments, through the stratum corneum of the skin into the body.Beneficial substances include, but are not limited to, pharmaceuticalagents, drugs, vitamins, co-factors, peptides, dietary supplements, andothers. The beneficial effects disclosed include, for instance, reliefof pain and inflammation, prevention and healing of ulcers of the skin,relief of headache, improved sexual function and enjoyment, growth ofhair on the scalp, improving muscle size and/or function, removing bodyfat and/or cellulite, treating cancer, treating viral infections andothers. A hostile biophysical environment may also be used inconjunction with systems and methods for increasing local blood flow,according to one set of embodiments. For example, by using a nitricoxide donor such as L-arginine, local blood flow may be increased, e.g.,by transdermally delivering the nitric oxide precursor. The nitric oxidedonor may be the sole cause of increased blood flow, or it may besupplemented with an adjunct such as theophylline.

The following documents are incorporated herein by reference: U.S.Provisional Patent Application Ser. Nos. 60/563,563, 60/563,558,60/563,559, 60/563,560, 60/563,561, 60/563,562, 60/563,572, 60/563,564,60/563,565, 60/563,566, 60/563,567, 60/563,553, 60/563,554, 60/563,555,60/563,556, 60/563,557, 60/563,551, 60/563,552, 60/563,569, 60/563,570,60/563,571, 60/563,573, 60/563,574, 60/563,575, and 60/563,576, eachfiled Apr. 19, 2004, by E. T. Fossel; U.S. Provisional PatentApplication Ser. No. 60/546,214, filed Feb. 23, 2004, entitled “TopicalDelivery of a Nitric Oxide Donor to Improve Body and Skin Appearance,”by E. T. Fossel; U.S. patent application Ser. No. 08/932,227, filed Sep.17, 1997, entitled “Topical Delivery of Arginine of Cause BeneficialEffects,” by E. T. Fossel, published as 2002/0041903 on Apr. 11, 2002;U.S. patent application Ser. No. 10/201,635, filed Jul. 22, 2002,entitled “Topical Delivery of L-Arginine to Cause Beneficial Effects,”by E. T. Fossel, published as 2003/0028169 on Feb. 6, 2003; U.S. patentapplication Ser. No. 10/213,286, filed Aug. 5, 2002, entitled “Topicaland Oral Arginine to Cause Beneficial Effects,” by E. T. Fossel,published as 2003/0018076 on Jan. 23, 2003; International PatentApplication No. PCT/US98/19429, filed Sep. 17, 1998, entitled “ADelivery of Arginine to Cause Beneficial Effects,” by E. T. Fossel,published as WO 99/13717 on Mar. 25, 1999; U.S. Pat. No. 5,895,658,issued Apr. 20, 1999, entitled “Topical Delivery of L-Arginine to CauseTissue Warming,” by E. T. Fossel; U.S. Pat. No. 5,922,332, issued Jul.13, 1999, entitled “Topical Delivery of Arginine to Overcome Pain,” byE. T. Fossel; U.S. Pat. No. 6,207,713, issued Mar. 27, 2001, entitled“Topical and Oral Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel; U.S. Pat. No. 6,458,841, issued Oct. 1, 2002, entitled“Topical and Oral Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel; International Patent Application No. PCT/US2005/005726,filed Feb. 23, 2005, entitled “Topical Delivery of a Nitric Oxide Donorto Improve Body and Skin Appearance,” by E. T. Fossel; and aninternational patent application filed on even date herewith, entitled“Use of Transdermal L-Arginine and Adjuncts to Cause Beneficial Effectsby Increasing Local Blood Flow,” by E. T. Fossel.

Detailed descriptions of the various embodiments are provided herein. Itis to be understood, however, that the present invention may be embodiedin various forms. Therefore, specific details disclosed herein are notto be interpreted as limiting, but rather as a basis for the claims andas a representative basis for teaching one skilled in the art to employthe present invention in virtually any appropriately detailed system,structure, or manner.

One aspect of the invention provides for the delivery of beneficialsubstances such as pharmaceutical agents (e.g., drugs, biologicalcompounds, etc.) into the body, and such treatments may be systemic orlocalized, e.g., directed to a specific location of the body, such asthe head, one or more specific muscles, the genitals, etc., depending onthe specific application.

In one set of embodiments, pharmaceutical agents are introduced to aidin treatment of medical conditions or diseases, and the symptomsassociated thereof. In some embodiments, the invention provides for thetreatment of medical conditions or diseases and/or ailments usingpharmaceutical agents (for example, to treat a subject diagnosed with amedical condition or disease, as described herein), and in some cases,the invention provides for the delivery of a minimum amount ofpharmaceutical agents to provide effective levels of medication to aneffected area topically while limiting side effects. In some cases, theeffective dosage of the pharmaceutical agent may be lower than theeffective dosage of the pharmaceutical agent when taken orally. Otherembodiments of the invention provides methods for treating cancer, viralinfections, erectile dysfunction, sexual dysfunction, an ulcer,swelling, or arthritis. Still another embodiment of the inventionprovides methods for treating pain, for example, pain from migraine,other headaches, joint pain, muscle pain and other types of pain. Yetanother embodiment of the present invention provides methods forrestoring hair growth, for example, on a portion of the scalp, which maybe scarce in hair.

Non-limiting examples of pharmaceutical agents include small molecules(e.g., having a molecular weight of less than about 2,000 Da, less thanabout 1,500 Da, or less than about 1,000 Da), peptides (e.g., havingless than about 10, less than about 15, less than about 20, or less thanabout 25 amino acids), proteins (typically larger than peptides),hormones, vitamins, nucleic acids, or the like. Additional examples ofsuitable pharmaceutical agents for use with the present inventioninclude, but are not limited to, NSAIDs (nonsteroidal anti-inflammatorydrugs) such as acetylsalicylsalicylic acid, naproxen, celecoxib,refecoxib, etc.; pharmaceutical agents with narcotic action such asmorphine, codine, propoxyphene, oxycodone, hydrocodon, or other similarnarcotics; pharmaceutical agents for erectile or sexual dysfunction suchas yohimbie, alprostadil, sildenafil, cialis, uprima, vardenaifl, or thelike; pharmaceutical agents for migraine such as dihydroergotamine andits salts, ergotamine and its salts, surnatripan and its salts,rizatriptan and its salts, zolmitriptan and its salts, etc.;pharmaceutical agents for hair treatment such as finasteride,eflornithine, minoxidil, or the like; or other pharmaceutical agentssuch as niacin, lidocaine, benzocaine, ibuprofen, etc. Additionalexamples include muscle improving agents, for example, creatine orcreatine precursors (e.g., creatine phosphate), arginine and/or othernitric oxide donors, and/or ATP precursors such as, inosine, adenosine,inosine, adenine, hypoxanthine, ribose, phosphate (e.g., monosodiumphosphate), etc., and/or anabolic steroid agents, such as androstene,DHEA, androstenediol, androstenedione, or the like. Another example isephedra or its components, such as ephedrine and pseudoephedrine. Yetanother example are chemotherapeutic agents or agents for treatingcancer and/or viral infections, for example, but not limited totamoxifen (e.g., for breast cancer treatment), cis-platin, carboplatinand related molecules, chclophosphamide and related molecules, vincaalkaloids, epipodophyllotoxins including taxol, acyclovir, or the like.For example, the cancer and/or viral infections may be skin cancer,breast cancer, penile cancer, testicular cancer, or other localizedcancers, or viral infections, such as herpes.

As a particular, non-limiting example, ibuprofen is an effective agentagainst pain when orally administered. However, it is irritating to thelining of the stomach, and people with a tendency to develop ulcers orhave an irritated upper gastrointestinal track are typically warned toavoid the use of ibuprofen. The present invention thus allows thetopical application of ibuprofen to the site of inflammation or pain,while avoiding the rest of the body, especially the stomach.

As another particular, non-limiting example, while growth hormones,steroids, supplements, and other such agents have been administeredorally and by injection to improve muscle size and function, thesemuscle improving agents are often distributed throughout the body,resulting in only a small portion of the agent acting at the muscle areabeing used and developed. Muscle requires both creatine phosphate (CrP)and adenosine triphosphate (ATP) to function. Often muscle hasinsufficient amounts of these substances and their precursors tomaintain high level function. Administration of these substances andtheir precursors have been attempted but in low dose that is ineffectiveand in high dose is both very expensive and produces side effects suchas gastrointestinal distress. Use of topical transdermal delivery to thedesired muscle or muscles of a muscle improving agent, according tovarious embodiments, may localize the dose to the desired area, andpotentially results in a higher concentration of the agent at thedesired area.

A variety of methods for effecting or improving absorption of beneficialsubstances (including pharmaceutical agents) are also included invarious aspects of the invention. In some cases, a hostile biophysicalenvironment may be used. In a hostile biophysical environment, theenvironment surrounding the beneficial substance may be such that thebeneficial substance is a chemically/energetically unfavorableenvironment, relative to the skin (e.g., the chemical potential and/orthe free energy of the beneficial substance within the hostilebiophysical environment is significantly greater than the chemicalpotential and/or the free energy of the beneficial substance within theskin, thus energetically favoring transport into the skin), especiallythe stratum corneum. The hostile biophysical environment which raisesthe chemical potential and/or the free energy of the beneficialsubstance can be comprised of a high ionic strength, a highconcentration of osmotic agents such as ureas, sugars, or carbohydrates,a high pH environment (e.g., greater than about 9, greater than about10, greater than about 11, greater than about 12, or greater than about13), a low pH environment (less than about 5, less than about 4, lessthan about 3 or less than about 2), highly hydrophobic components, orhighly hydrophilic components or other substances that cause an increasein the chemical potential and/or free energy of the beneficialsubstance. A hydrophobic component may have an octanol-water partitioncoefficient of at least about 100, at least about 1000, at least about10⁴, at least about 10⁵, or more in some cases. Similarly, a hydrophiliccomponent may have an octanol-water partition coefficient of less thanabout 0.01, less than about 10⁻³, less than about 10⁻⁴, or less thanabout 10⁻⁵ in some cases.

In some cases, the delivery vehicle defines the biophysical hostileenvironment. In other cases, the beneficial substance may be packaged insuch a way that it is carried into tissue and/or its charge isneutralized by derivitization and/or by forming a neutral salt. Examplesof biophysically hostile environments include, but are not limited to,high ionic strength environments (e.g., by the addition of ureas,sugars, carbohydrates, and/or ionic salts such as lithium chloride,sodium chloride, potassium chloride, calcium chloride, magnesiumchloride, choline chloride, sodium fluoride, lithium bromide, etc., aswell as combinations of these and/or other agents, for instance at highionic strengths (for example, greater than about 0.25 M, greater thanabout 1 M, greater than about 2 M, greater than about 3 M, greater thanabout 5 M, greater than about 10 M, greater than about 15 M, greaterthan about 20 M, greater than about 25 M, etc., or in some cases,between about 0.25 M and about 15 M, between about 5 M and about 15 M,between about 10 M and about 15 M, etc.); high or low pH environments(e.g., by adding pharmaceutically acceptable acids or bases, forexample, such that the pH is between about 3 and about 7, between about3 and about 6, between about 3 and about 5, between about 7 and about11, between about 8 and about 11, between about 9 and about 11, etc.);or highly hydrophobic environments (e.g., by decreasing water contentand increasing lipid, oil and/or wax content of the environment). Otherhighly charged molecules such as polylysine, polyglutamine,polyaspartate, etc., or copolymers of such highly charged amino acidsmay also be used in certain embodiments to create the hostilebiophysical environment. Non-limiting examples of packaging which wouldbe carried into tissue includes liposomes or emulsions of collagen,collagen peptides or other components of skin or basement membrane.Non-limiting examples of neutralization of charge include delivery ofthe beneficial substance in the form or an ester or salt which iselectronically neutral. In some embodiments, the hostile biophysicalenvironment may include any two or more of these conditions. Forinstance, the hostile biophysical environment may include high ionicstrength and a high pH or a low pH, a highly hydrophobic environment anda high pH or a low pH, a highly hydrophobic environment that includesliposomes, or the like.

A hostile biophysical environment may also be created in someembodiments by placing a beneficial substance that is relatively highlycharged into a hydrophobic, oily environment such as in an oil-basedcream or lotion containing little or no water. Absorption may further beaided by combining the use of hostile biophysical environments with theuse of penetrating agents, as further described below.

It should be noted that a hostile biophysical environment optimized forone beneficial substance may not necessarily be optimal for anotherbeneficial substance. For example, an optimal hostile biophysicalenvironment for a beneficial substance that is non-charged and does notform hydrogen bonds, in one embodiment of the invention, may notnecessarily be optimal for other embodiments of the invention, in whicha beneficial substance is charged, and/or in embodiments in which thebeneficial substance is able to form hydrogen bonds. Thus, differenthostile biophysical environment(s) may be prepared or optimized fordifferent application(s) including different beneficial substance(s)being delivered using the hostile biophysical environment(s).

In certain aspects of the invention, a pharmaceutical agent or otherbeneficial substance may be combined with a penetrating agent, i.e., anagent that increases transport of the pharmaceutical agent or otherbeneficial substance into the skin, relative to transport in the absenceof the pharmaceutical agent or other beneficial substance. In someembodiments, the penetrating agent may be combined with a hostilebiophysical environment. Examples of penetrating agents includeoleoresin capsicum or its constituents, or certain molecules containingheterocyclic rings to which are attached hydrocarbon chains.

Non-limiting examples of penetrating agents include, but are not limitedto, cationic, anionic, or nonionic surfactants (e.g., sodium dodecylsulfate, polyoxamers, etc.); fatty acids and alcohols (e.g., ethanol,oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g.,benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane);amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g.,n-butyrate); organic acids (e.g., citric acid); polyols (e.g., ethyleneglycol, glycerol); sulfoxides (e.g., dimethylsulfoxide); terpenes (e.g.,cyclohexene); ureas; sugars; carbohydrates or other agents. In oneembodiment, the penetrating agent includes a salt, e.g., as previouslydescribed.

The present invention, in one aspect, provides various systems andtechniques for increasing local blood flow. For example, increased bloodflow may be used to introduce pharmaceutical agents (e.g., drugs,biological compounds, etc.) to aid in treatment of medical conditions ordiseases and the symptoms associated thereof (for example, to treat asubject diagnosed with a medical condition or disease, as describedherein), and/or the increased blood flow may be used to provideeffective treatment of medical conditions or diseases and/or ailmentswith the minimum amount of pharmaceutical agents possible to provideeffective levels of medication to an effected area topically whilelimiting side effects. In one set of embodiments, a nitric oxide donorsuch as L-arginine and/or L-arginine hydrochloride in an effectiveconcentration may be used to increase localized blood flow, which mayenhance delivery of a pharmaceutical agent or other beneficialsubstance, e.g., to locally afflicted tissue. Nitric oxide may relax theblood vessels, allowing for increased blood flow. In some cases, one ormore nitric oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitricoxide donors) may be combined with one or more beneficial substances(e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. beneficial substances) in asuitable hostile biophysical environment, as described herein.

Besides L-arginine and L-arginine hydrochloride, other non-limitingexamples of nitric oxide donors include D,L-arginine, D-arginine, oralkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, etc.) esters of L-arginine and/or D-arginine (e.g., a methylester, an ethyl ester, a propyl ester, a butyl ester, etc.) and/or saltsthereof, as well as other derivatives of arginine and other nitric oxidedonors. For instance, non-limiting examples of pharmaceuticallyacceptable salts include hydrochloride, glutamate, butyrate, orglycolate (e.g., resulting in L-arginine glutamate, L-arginine butyrate,L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate,etc.). Other examples of nitric oxide donors include L-arginine-basedcompounds such as, but not limited to, L-homoarginine,N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated L-arginine,nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,citrulline, omithine, linsidomine, nipride, glutamine, etc., and saltsthereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.).Still other non-limiting examples of nitric oxide donors includeS-nitrosothiols, nitrites, 2-hydroxy-2-nitrosohydrazines, or substratesof various forms of nitric oxide synthase. In some cases, the nitricoxide may be a compound that stimulates endogenous production of nitricoxide in vivo. Examples of such compounds include, but are not limitedto, L-arginine, substrates of various forms of nitric oxide synthase,certain cytokines, adenosine, bradykinin, calreticulin, bisacodyl,phenolphthalein, OH-arginine, or endothelein.

It should be understood that, in any of the embodiments described hereinthat describe L-arginine, other nitric oxide donors may also be usedinstead, or in combination with, L-arginine, in other embodiments of theinvention.

Without wishing to be bound to any theory, it is generally believed thatthe flow of the pharmaceutical agent or other beneficial substanceacross the skin may slow as it builds up within the tissue. Fick's firstlaw of diffusion suggests that when the concentration inside becomessubstantially equal to that outside, passive flow stops. The increasedlocal blood flow may prevent or at least decrease the stoppage of theflow of the pharmaceutical agent or other beneficial substance. Thus,when the vehicle containing the pharmaceutical agent or other beneficialsubstance and a nitric oxide donor, such as L-arginine, is applied tothe skin, the pharmaceutical agent or other beneficial substance exitsthe vehicle into the tissue more readily, as the pharmaceutical agent isdispersed by flow and does not build up in concentration in the tissue.Thus, in certain embodiments, pharmaceutical agents or other beneficialsubstances may be introduced into the skin, for example, ibuprofen,anabolic steroids, or other agents or substances described herein.

One set of embodiments provides for increased blood flow to thegenitals, for example, using a nitric oxide donor such as L-arginine,optionally in combination with a silicon-based transdermal preparationand/or an adjunct such as theophylline. Adequate local genital bloodflow is important for optimal sexual function and satisfaction in bothmen and women. In men it is important to achieve and maintain anerection. In women it is important for nerve sensitivity which isrequired to attain satisfying orgasms. In some cases, the preparationmay be contained within a condom, optionally with other sexual-enhancingagents, such as lubricants.

A non-limiting example of such a preparation includes a silicon-basedvehicle (e.g., a vehicle that contains a silicon-containing substance)with properties of excellent absorption into the skin which alsocontains L-arginine hydrochloride (7.5% w/v), theophylline (5% w/v) anda mixture of high molecular weight polydimethylsiloxane and a lowviscosity cyclotetrasiloxane (commercially known as Dow Corning 1411fluid), and water prepared as an emulsion. The silicon emulsion providesa hostile biophysical environment in this example. The emulsion isapplied to the genitals (e.g., the penis, or the clitoris and/or thevagina) and rubbed in until absorbed. The emulsion may facilitateenhanced blood flow to the genitals, bringing oxygen and other nutrientsand blood to that tissue. In addition, the silicon may act as alubricant for improved enjoyment of sexual function. Additionalpreparations are discussed in more detail herein. Other examples ofsilicon-containing substances include polydimethylsiloxane,cyclopentasiloxane, dimethicol, or dimethicon. For example, apreparation of the invention may be a cream containing water (20-80%), apolydimethylsiloxane/cyclopentasiloxane mixture (20-90% w/v) and TWEEN20 (1-10%), and the pH may be between about 3 and about 11.

A “nitric oxide donor,” as used herein, is a compound that containstherein a nitric oxide (NO) moiety, where the compound is able torelease nitric oxide and/or chemically transfer the nitric oxide moietyto another molecule, directly or indirectly, for example, through abiological process. The nitric oxide donor may release nitric oxide intothe skin, and/or tissues such as muscles and/or elements of thecirculatory system in close proximity to the surface of the skin.Non-limiting examples of nitric oxide donors include arginine (e.g.,L-arginine and/or D-arginine), arginine derivatives (e.g., L-argininehydrochloride and/or D-arginine hydrochloride), nitroglycerin,polysaccharide-bound nitric oxide-nucleophile adducts,N-nitroso-N-substituted hydroxylamines,1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, etc., as described in moredetail herein. In some cases, the concentration of nitric oxide and/orthe nitric oxide donor may be tailored to have a duration of effectivetreatment of at least about 3 hours, at least about 5 hours, or at leastabout 8 hours or more in certain instances. The duration may also becontrolled, for instance, by controlling the concentration of apenetrating agent used in conjunction with nitric oxide and/or thenitric oxide donor. The actual concentration for a particularapplication can be determined by those of ordinary skill in the artusing no more than routine experimentation, for example, by measuringthe amount of transport of nitric oxide and/or the nitric oxide donor asa function of concentration in vitro across cadaver skin or suitableanimal models, skin grafts, synthetic model membranes, or the like.

As a particular non-limiting example, in one embodiment, nitric oxide isprovided using L-arginine, for example, at a concentration of at leastabout 0.5% by weight (wt % or w/v) of L-arginine (optionally with one ormore penetrating agents as discussed herein, for example, a penetratingagent able to create a hostile biophysical environment), at least about0.75 wt %, at least about 1 wt %, at least about 2 wt %, at least about3 wt %, at least about 5 wt %, at least about 7 wt %, at least about 10wt %, or at least about 15 wt %. The L-arginine may be present in asuitable delivery vehicle, such as a cream or a lotion. L-arginine maybe particularly useful in some cases due to its low toxicity, its highsolubility, or its low cost. Other examples of nitric oxide donors arediscussed in International Patent Application No. PCT/US2005/005726,filed Feb. 23, 2005, entitled “Topical Delivery of a Nitric Oxide Donorto Improve Body and Skin Appearance,” by E. T. Fossel, incorporatedherein by reference.

Thus, another aspect of the invention provides for the delivery ofnitric oxide and/or nitric oxide donors into the body, as furtherdescribed below, and such treatments may be systemic or localized, e.g.,directed to a specific location of the body, such as the head, arms,legs, feet, etc., depending on the specific application. The nitricoxide and/or nitric oxide donor may increase local blood flow, therebyenhancing tissue health. Increased blood flow may also assist in thehealing process, e.g., where injury or surgery has occurred.

In one set of embodiments, nitric oxide and/or a nitric oxide donor(e.g., arginine and/or an arginine derivative), optionally including anadjunct such as theophylline, may be applied to a subject to improve theoutcome of various medical conditions, such as surgical treatments(e.g., at a site of surgery). Non limiting for examples includetransplant and plastic surgery, graft sites of real or artificial skin,or other surgically treated areas. In some embodiments of the invention,a treatment of the invention may be applied to improve flow inperipheral artery disease and/or prevent claudication, to improve thecirculation in the feet of people with diabetes and others with impairedcirculation, to regress neuropathy, to heal or prevent ulcers, toimprove bone healing, to treat infection (e.g., bacterial infections,viral infections, fungal infections, etc.), to improve grafting of realor artificial skin, and/or to improve wound healing, and/or to improve asurgically treated area.

In another set of embodiments, nitric oxide and/or a nitric oxide donor(e.g., arginine and/or an arginine derivative), optionally including anadjunct such as theophylline, may be applied to a subject havingperipheral artery disease (PAD), for example, in subjects treatedinvasively or non-invasively. For instance, arteries are often reopenedby use of angioplasty, arthectomy or bypass surgery, or through the useof intravenous drug treatments, such as Corlapam, Flolan, or Primacor.Left untreated or unsuccessfully treated, PAD can lead to claudication,which can be incapacitating, resulting not only in great pain but lossof the ability to carry on a normal life. Various systems and methods ofthe present invention can be used in some cases, as a replacement forand/or in conjunction with such methods of treatment.

Yet another set of embodiments provides for the enhancement of bonehealing by increasing local blood flow. Bone healing is a slow andcomplex process, and it is enhanced by a variety of proteins and cellsin the blood. An increase in blood flow rate may thus enhance bonehealing. In some cases, the application of a nitric oxide and/or anitric oxide donor (e.g., arginine and/or an arginine derivative),optionally including an adjunct such as theophylline, may increase bloodflow to the bone. Thus, for example, a fractured bone (including abroken bone) may be treated in certain embodiments of the invention.

In still another set of embodiments, an infection may be treated byincreasing local blood flow. The body fights infection using cells andcell derived materials found in the blood. Increasing blood flow to thesite of an infection can enhance the body's mechanisms for fightinginfection. Thus, the application of a nitric oxide and/or a nitric oxidedonor (e.g., arginine and/or an arginine derivative), optionallyincluding an adjunct such as theophylline, may increase blood flow tothe site of infection, which may promote healing.

Another set of embodiments is generally directed to the treatment ofblood flow in persons with diabetes, e.g., in the hands and/or feet. Theapplication of a nitric oxide and/or a nitric oxide donor (e.g.,arginine and/or an arginine derivative), optionally including an adjunctsuch as theophylline, may be used to treat such conditions, therebyincreasing blood flow within the hands and/or feet. In some cases, longlasting improvement in blood flow, and/or regression of diabeticneuropathy may be achieved. For example, local blood flow may beincreased by at least about 20% or at least about 30%. Still another setof embodiments of the invention are directed to the prevention ortreatment of diabetic skin ulcers, e.g., by increasing blood flow, aspreviously described.

In still another set of embodiments, nitric oxide and/or a nitric oxidedonor (e.g., arginine and/or an arginine derivative), optionallyincluding an adjunct such as theophylline, may be applied to the skin,for example, to a skin graft and/or graft material of a skin graft, to awound in the skin, etc. Often, skin grafts do not have sufficient bloodflow, which may lead to graft failure. By enhancing the blood flow tothe skin graft, e.g., using the nitric oxide and/or a nitric oxidedonor, graft failure may be reduced. In some cases, the nitric oxideand/or nitric oxide donor may be applied to tissues proximate the skingraft, and/or the nitric oxide and/or nitric oxide donor may be inducedto migrate to tissues adjacent the skin graft.

Another set of embodiments of the invention is directed to treatingmedical conditions by not only enhancing blood flow to a treated regionof the body, but also by enhancing transdermal delivery of apharmaceutical agent or other beneficial substance through the use of anitric oxide and/or a nitric oxide donor (e.g., arginine and/or anarginine derivative), optionally including an adjunct such astheophylline, to increase blood flow at the site of molecular transport.Such embodiments may be relatively simple, inexpensive, and/ornon-irritating, and in many cases, no physical or mechanical devices arerequired. Such transport may be further increased, for example, incombination with penetrating agents or the like, as described herein.

In some aspects of the invention, a nitric oxide and/or nitric oxidedonor, and/or a pharmaceutical agent or other beneficial substance, maybe administered using a delivery vehicle such as a cream, gel, liquid,lotion, spray, aerosol, or transdermal patch. Examples of deliveryvehicles are discussed below. The delivery vehicle may promote transferinto the skin of an effective concentration of the nitric oxide and/ornitric oxide donor, and/or a pharmaceutical agent or other beneficialsubstance, directly or indirectly. For instance, the delivery vehiclemay include one or more penetrating agents, as further described herein.In some embodiments, the delivery vehicle may include a hostilebiophysical environment, e.g., using a penetrating agent, etc., asdescribed herein. Those of ordinary skill in the art will know ofsystems and techniques for incorporating a nitric oxide and/or nitricoxide donor, and/or a pharmaceutical agent or other beneficial substancewithin delivery vehicles such as a cream, gel, liquid, lotion, spray,aerosol, or transdermal patch. In some cases, the concentration of thenitric oxide and/or nitric oxide donor, and/or a pharmaceutical agent orother beneficial substance in the delivery vehicle can be reduced withthe inclusion of a greater amount or concentration of penetrating agent,or increased to lengthen the beneficial effect. In one set ofembodiments, the nitric oxide and/or nitric oxide donor, and/or apharmaceutical agent or other beneficial substance may be used inconjunction with an adjunct, such as theophylline (for example, at 10%weight by volume).

Other materials may be present within the delivery vehicle, for example,buffers, preservatives, surfactants, etc. For instance, the cream mayinclude one or more of water, mineral oil, glyceryl stereate, squalene,propylene glycol stearate, wheat germ oil, glyceryl stearate, isopropylmyristate, steryl stearate, polysorbate 60, propylene glycol, oleicacid, tocopherol acetate, collagen, sorbitan stearate, vitamin A and D,triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea,propylparaben, PND, or BHA.

As specific non-limiting examples, the cream may have one or more of(w/v): water (20-80%), white oil (3-18%), glyceryl stearate (0.25-12%),squalene (0.25-12%), cetyl alcohol (0.1-11%), propylene glycol stearate(0.1-11%), wheat germ oil (0.1-6%), polysorbate 60 (0.1-5%), propyleneglycol (0.05-5%), collagen (0.05-5%), sorbitan stearate (0.05-5%),vitamin A (0.02-4%), vitamin D (0.02-4%), vitamin E (0.02-4%),triethanolamine (0.01-4%), methylparaben (0.01-4%), aloe vera extract(0.01-4%), imidazolidinyl urea (0.01-4%), propylparaben (0.01-4%), BHA(0.01-4%), L-arginine Hydrochloride (0.25-25%), sodium chloride(0.25-25%), magnesium chloride (0.25-25%), and/or choline chloride(0.25-25%). The percentages of each compound can vary (or the compoundmay be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In another embodiment, the cream may include a beneficial substance,such as ibuprofen, and one or more of the following: water (20-80%),L-arginine hydrochloride (0-25%), sodium chloride (0-25%), potassiumchloride (0-25%), glyeryl steareate (0-15%), cetyl alcohol (0-15%),squalene (0-15%), isopropyl mysterate (0-15%), oleic acid (0-15%), Tween20 (0-10%), and/or butanediol (0-10%). The percentages of each compoundcan vary (or the compound may be absent in some cases), for example, 1%,2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In some embodiments, the cream may include a beneficial substance, andone or more ionic salts at a concentration at least sufficient toproduce a hostile biophysical environment with respect to the beneficialsubstance. For example, the cream may include one or more of (w/v): acharged and/or hydrogen bonding beneficial substance with systemictoxicity (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%),and/or magnesium chloride (1-20% w/v). In another example, the cream mayinclude one or more of (w/v): L-arginine hydrochloride (2.5-25%),choline chloride (10-30%), sodium chloride (5-20%), and/or magnesiumchloride (5-20%). In still another example, the cream may include one ormore of (w/v): creatine (0.001-30%), inosine (0.001-30%), cholinechloride (1-30%), sodium chloride (2-30%), magnesium chloride (1-20%),L-arginine (0.1-25%), and/or theophylline (0.1-20%). In some cases, thecream may also contain L-arginine hydrochloride (0-12.5% w/v) and/ortheophylline (0-10% w/v). The percentages of each compound can vary (orthe compound may be absent in some cases), for example, 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc. In theseexamples, choline chloride, sodium chloride and magnesium chloride canprovide a high ionic strength environment.

In certain aspects of the invention, multiple treatments of the deliveryvehicle may increase the duration of the effects of the beneficialsubstance, for example two, three, four, five, or more treatments may beapplied, depending on the particular application. For example, withrepeated administrations, the beneficial effects of each treatment maybe extended up to ten or twenty hours after treatment, or more in somecases. Such treatments may be given at any suitable frequency, dependingon the particular application, for example, every 4 hours, every 8hours, every 12 hours, every 18 hours, every 1 day, every 2 days, every3 days, every week, etc. For instance, the treatment may be providedbetween about 2 and about 30 times within a time period of about 30days. In some cases, the first treatment may be given at a higher levelor concentration than subsequent treatments.

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

Example 1

In this example, a 57 year old woman with severe arthritis in her handsand fingers applied a cream comprising a hostile biophysicalenvironment, along with 10% w/v ibuprofen and 12.5% w/v L-arginine, toher hands. She rubbed the cream into the skin of her hands and fingersuntil completely absorbed. Within 10 minutes she noticed substantialrelief from the pain. Within 30 minutes the pain was completely gone.Pain relief persisted for several hours.

Example 2

In this example, a 37 year old man with shoulder pain applied a creamcomprising a hostile biophysical environment, along with 10% w/vibuprofen and 12.5% w/v L-arginine, to the painful shoulder. He rubbedthe cream in until it was completely absorbed. Within 30 minutes thepain was completely gone. The pain never returned.

Example 3

A 54 year old woman with a severe headache in her right temple applied acream comprising a hostile biophysical environment, 10% w/v ibuprofen,and 12.5% w/v L-arginine to the painful temple. She rubbed the cream inuntil completely absorbed. Within 10 minutes substantial relief of theheadache was achieved. Within 20 minutes the pain was gone. The painnever returned.

Example 4

A 33 year old woman with a history of genital herpes infection wastreated with a topical transdermal preparation of acyclovir. Herpes ischaracterized by outbreaks which start as a red, sometimes itching areaand progress to open sores. The acyclovir preparation included a hostilebiophysical environment, 2.5% w/v acyclovir, and 12.5% w/v L-Arginine.This preparation was applied as soon as the red and sometimes itchingareas appeared. This treatment resulted in regression of the insipientherpes outbreak, returning the area to normal within two days andpreventing the open sores from developing.

Example 5

A 58 year old man suffering from claudication of the lower leg applied acream comprising L-arginine hydrochloride (12.5% w/v), choline chloride(10% w/v), magnesium chloride (5% w/v), and sodium chloride (5% w/v) ina penetrating base to his legs nightly. After using it daily for threedays, the cramps from claudication never recurred as long as hecontinued daily use of the cream.

Example 6

A 72 year old man with a twelve year history of PAD and claudicationseverely incapacitating him was treated in this example. He began dailyuse of a cream containing L-arginine hydrochloride (12.5% w/v), cholinechloride (10% w/v), magnesium chloride (5% w/v), and sodium chloride (5%w/v) in a penetrating base to his lower legs. After three days of usethe frequency of the attacks were markedly reduced, and after ten daysthe attacks had ceased. Continued daily use of the cream continued toprevent attacks.

Example 7

Circulatory impairment and its sequlae have long been known to be amajor complication of diabetes. For instance, it has been shown that, indiabetes, the functionality of the endothelial nitric oxide (NO)/nitricoxide synthase (eNOS) system is impaired. NO is generated in theendothelium through the oxidation of the amino acid, L-arginine by theenzyme eNOS. NO causes vascular smooth muscle to relax resulting inincreased blood flow. In addition to being a substrate of eNOS,L-Arginine facilitates the dimerization of two identical subunits ofeNOS, forming a homodimer. The enzyme is only active in the dimericform. Under proper conditions, dimerization occurs rapidly, on atimescale of minutes. Once formed the dimer is generally stable.

Subjects with diabetes may have abnormally low levels of L-Arginine andelevated levels of the eNOS inhibitor, asymmetric dimethylarginine(ADME) in their plasma. Though the value of increasing L-Arginine levelsin cases of impaired circulation is now recognized, practical schemesfor therapeutic use of L-Arginine have been illusive. In this example,it was determined whether supplying L-Arginine transdermally wouldimprove vascular function of the feet in patients with diabetes, asindicated by flow and temperature.

The example was designed as a double-blind vehicle-controlled two-periodcrossover protocol, with washout periods of one week. Sixteen subjectswere enrolled and thirteen completed the study (age 56+/−8 yr). Afteranalyzing the data it was shown that the effect of L-arginine persistedthroughout the washout periods (Tables 1 and 2, AU standing forArbitrary Units). Because of this, except for the initial exposure ofL-arginine on virgin feet, the analysis was altered to determine theeffect from cumulative exposure to L-arginine throughout the protocol.Blood flow was measured at the metatarsal and Achilles area using aDoppler flow meter, and temperature was measured at the metatarsal andbig toe areas using an infrared thermometer. The active cream was awater-based moisturizing vehicle containing 12.5% L-argininehydrochloride in a hostile biophysical environment comprising a highconcentrations of choline chloride, sodium chloride and magnesiumchloride. The control vehicle was identical, except that the L-argininewas omitted.

At the first visit, after baseline measurements were made each subjectrubbed active cream (4 mg of L-arginine/cm²) into one foot and vehicleinto the other. After thirty minutes measurements were made again. A oneweek wash out period followed. Patients returned after the wash outperiod and flow and temperature measurements were made. They were thenrandomly given either active or placebo cream and told to rub it intotheir feet in the morning and evening every day for two weeks. At theend of two weeks subjects returned and again measurements were made. Asecond one week wash out period followed that third visit. At the end ofthat period subjects returned and measurements were made. They weregiven the cross over product and told again to rub it into their feetmorning and evening for two weeks. The subjects returned for final flowand temperature measurements at the end of that period.

At the first visit flow was increased at the Achilles in the foot withactive cream from 8.1+/−3.3 to 11.5+/−5.5 (p=0.05) thirty minutes afterapplication. In the foot that received placebo cream flow failed toincrease (8.1+/−1.4 vs. 8.3+/−2.2). Further, at the last visit thetemperature at the metatarsal area had risen from the initial value of82.0+/−2.3 to 86.9+/−2.4 (p<0.0001) and the temperature of the big toehad risen from the initial visit value of 74.4+/−4.2 to 82.4+/−4.8(p<0.0001). At the last visit the flow at the metatarsal area had risenfrom 8.7+/−4.3 to 11.6+/−5.5 (p<0.0001) and flow at the Achilles areahad risen from 8.4+/−2.5 to 11.4+/−5.5 (p=0.02). While the failure ofthe L-arginine effect to wash out removed the opportunity for placebocontrol, the improvement in temperature and flow were substantial andhighly statistically significant. Though puzzling, one explanation ofthe persistence of the L-arginine effect is that the local tissueconcentration of L-arginine becomes high enough to cause inactivemonomers of eNOS to form active dimers.

Thus, in the patients studied in this example with diabetes, treatmentof their feet with a transdermal preparation of L-arginine improved bothflow and temperature, and this effect was surprisingly long lasting.Such improvement of compromised local blood flow would be beneficial andcould reduce the complications of the disease.

TABLE 1 Effect of Transdermal L-Arginine Cream on Temperature p vs. p vsMetatarsal (° F.) Visit 1 Big Toe (° F.) Visit 1 Visit 1 82.0 +/− 2.374.4 +/− 4.2 Visit 2 84.1 +/− 3.4 0.004 77.7 +/− 5.3 0.01 Visit 3 87.0+/− 2.4 <0.0001 83.6 +/− 4.9 <0.0001 Visit 4 86.1 +/− 2.4 <0.0001 80.6+/− 5.4 <0.0001 Visit 5 86.9 +/− 2.4 <0.0001 82.4 +/− 4.8 <0.0001

TABLE 2 Effect of Transdermal L-Arginine Cream on Flow p vs. p vs.Metatarsal (AU) Visit 1 Achilles (AU) Visit 1 Visit 1  8.7 +/− 4.3 8.4+/− 2.5 Visit 2 10.8 +/− 5.9 NS 8.5 +/− 3.9 NS Visit 3 10.8 +/− 4.8 0.059.2 +/− 3.9 NS Visit 4 11.6 +/− 8.3 NS 10.0 +/− 4.2  0.06 Visit 5 11.6+/− 5.5 <0.0001 11

Example 8

This example illustrates one method of preparing a transdermal formulaof the invention including ibuprofen. The final composition is shown inTable 3. Of course, those of ordinary skill in the art will understandthat percentages other than the ones listed below are also possible,according to other embodiments of the invention.

TABLE 3 Example of a Transdermal Preparation Water 49% L-ArginineHydrochloride 7.5% Ibuprofen (sodium salt) 7.5% Sodium Chloride 10%Potassium Chloride 5% Glyeryl Steareate (SE) 7% Cetyl Alcohol 7%Squalene 2% Isopropyl Mysterate 1% Oleic Acid 1% Tween 20 2% Butanediol1%

To prepare the formulation in this example, sodium chloride, potassiumchloride, L-arginine and ibuprofen were mixed in water, then heated to74 degrees C. with rapid mixing. In a separate container, the remainingingredients were mixed together and heated to 74 degrees C. The otheringredients were then added to the water phase at 74 degrees C. withrapid mixing. The mixture was then cooled to room temperature withcontinued mixing. At this point, an emulsion formed with a relativelythin consistency. The emulsion was then homogenized at high speed atroom temperature to thicken the consistency.

According to aspects of the invention described and illustrated herein,beneficial substance(s) (e.g., pharmaceutical agent(s)) may be provided(e.g., in a delivery vehicle) at a concentration of between about 0.1%and about 25% (for example at a concentration of 0.1%, 0.5%, 1%, 2%, 3%,4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.).However, higher (e.g., above 25%, 30%, 40%, 50% or higher) or lower(e.g., below 0.1%, 0.05% or lower) concentrations of beneficialsubstance(s) may be used. As used herein (for a beneficial substance orany other compound described herein) a concentration % may be a % byweight, a % by volume, or a % weight by volume. As used herein, abeneficial substance may be, for example, a charged beneficialsubstance, a non-charged beneficial substance, a beneficial substancethat forms hydrogen bonds, a beneficial substance that does not formhydrogen bonds, etc.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is:
 1. A topical delivery vehicle, comprising: a nitricoxide donor; and a pharmaceutical agent comprising sildenafil, whereinthe topical delivery vehicle has an ionic strength of between about 0.25M and about 15 M.
 2. (canceled)
 3. The topical delivery vehicle of claim1, wherein the nitric oxide donor comprises L-arginine.
 4. The topicaldelivery vehicle of claim 1, wherein the nitric oxide donor comprisesL-arginine hydrochloride.
 5. The topical delivery vehicle of claim 1,wherein the nitric oxide donor comprises an L-arginine salt.
 6. Thetopical delivery vehicle of claim 1, wherein the topical deliveryvehicle comprises an ionic salt.
 7. The topical delivery vehicle ofclaim 6, wherein the ionic salt comprises one or more of sodiumchloride, choline chloride, magnesium chloride, lithium chloride, andcalcium chloride.
 8. The topical delivery vehicle of claim 1, whereinthe topical delivery vehicle has a pH of between about 3 and about 11.9. The topical delivery vehicle of claim 1, wherein the topical deliveryvehicle comprises citric acid.
 10. The topical delivery vehicle of claim1, wherein the ionic strength is at least 1 M.
 11. The topical deliveryvehicle of claim 1, wherein the topical delivery vehicle is containedwithin a condom.
 12. The topical delivery vehicle of claim 11, whereinthe topical delivery vehicle further comprises a lubricant.
 13. Thetopical delivery vehicle of claim 1, wherein the topical deliveryvehicle is a cream.
 14. The topical delivery vehicle of claim 1, whereinthe topical delivery vehicle is a gel.
 15. The topical delivery vehicleof claim 1, wherein the topical delivery vehicle is a lotion.
 16. Atopical delivery vehicle having an ionic strength of at least about 1 Mand comprising sildenafil, citric acid, and a nitric oxide donorselected from the group consisting of L-arginine and L-argininehydrochloride.
 17. The topical delivery vehicle of claim 16, wherein thetopical delivery vehicle is a cream.
 18. The topical delivery vehicle ofclaim 16, wherein the nitric oxide donor is present at a concentrationof at least 0.5% by weight/volume.
 19. The topical delivery vehicle ofclaim 16, wherein the topical delivery vehicle is contained within acondom.
 20. A method, comprising: administering a topical deliveryvehicle to the genitals of a human subject, the topical delivery vehiclehaving an ionic strength of at least about 1 M and comprisingsildenafil, and a nitric oxide donor selected from the group consistingof L-arginine and L-arginine hydrochloride. 21-22. (canceled)
 23. Themethod of claim 20, wherein the nitric oxide donor is present at aconcentration of at least 0.5% by weight/volume.
 24. The method of claim20, wherein the topical delivery vehicle comprises citric acid.
 25. Themethod of claim 20, wherein the human subject is male and the genitalsis the penis.
 26. The method of claim 25, comprising applying a condomto the penis, wherein the condom comprises the topical delivery vehicle,thereby administering the topical delivery vehicle to the penis of themale human subject.
 27. The method of claim 20, wherein the topicaldelivery vehicle is a cream.